Monoclonal antibodies

ABSTRACT

The present invention provides DNA sequences encoding complementarity determining regions of variable domains of human anti-RhD antibodies and their use in the production of recombinant chimaeric antibody molecules.

This invention relates to novel monoclonal anti-RhD antibodies preparedby recombinant DNA methods.

The Rhesus blood group system is a major antigenic constituent of thehuman red blood cell membrane; of this group, the RhD antigen is ofparticular clinical importance in relation to isoimmune reactions. An RhD-individual with anti-RhD who receives RhD+ blood is liable to suffersubstantial red blood cell (RBC) destruction due to the RhD phenotypeincompatibility, and thus blood of donors must routinely be classifiedas RhD+ or RhD-. Anti RhD monoclonal antibodies (anti-D Mabs) arecapable of providing blood-typing reagents of high specificity andreliability.

The RhD antigen is also responsible for haemolytic disease of thenewborn (HDN). This condition arises in newborn RhD+ infants of RhD-mothers previously sensitised to RhD Antigen as a result of IgG anti-RhDantibodies crossing the placenta during pregnancy and causing foetal redblood cell (RBC) destruction. Sensitization of the RhD- mother to RhDantigen often occurs during the birth of an earlier RhD+ child due tosome foetal RBCs entering the maternal circulation and being recognisedas foreign by the maternal immune system. To reduce the incidence ofHDN, it is routine practice in the United Kingdom and many othercountries to give anti-RhD antibodies to RhD- mothers immediately afterthe birth of an RhD+ infant so that any RhD+ RBCs which may have enteredthe maternal circulation are rapidly removed.

The search for the most effective anti D Mabs has proved to be extremelytime consuming, involving the isolation of B-lymphocytes from humansimmunised against RhD, usually Rh-ve mothers who have given birth toRh+ve children. Such lymphocytes are subjected to EBV treatment toprovide an immortalised cell-line directly or the EBV-treated cells arehybridised with suitable mouse myeloma cells to provide a hydridoma: Thecell-line line or hybridoma may then be used to produce the anti-D Mabin the conventional way.

However, there are significant differences between anti-D Mabs in termsof their binding affinities for red cells, their ability to recogniseD-variants such as D^(u) and D^(VI), and their ability to destroy targetcells by phagocytosis or cell-mediated lysis. It is desirable,therefore, to have available a method of combining the favourableparameters of different anti-D Mabs or, indeed of combining the mostfavourable features of selected anti-D Mabs with Mabs of quite differentspecificities which present particular advantages, in order to produceso-called chimaeric Mabs.

The concept of building chimaeric Mabs, has been described by Jones etal (Nature 321, 522-525 (1986)) and Riechmann et al (Nature 332, 323-327(1988)). Three dimensional studies have shown that immunoglobulinscomprise essentially constant regions common to most Mabs and terminallysituated variable domains associated with antigen binding.

It has been shown that the variable domains consist of two β-sheetsjoined by a disulphide bridge with their hydrophobic faces in contact.Sequence comparisons among heavy- and light-chain variable domains(V_(H) and V_(L) respectively) have revealed that each of these domainscomprises three hypervariable domains or complementarity determiningregions (CDRs) set in a framework of four relatively conserved regions,the framework regions (FRs). The CDRs are primarily responsible for therecognition of specific antigens. The structure of the β-sheet frameworkis similar in different antibodies, as the packing together of V_(L) andV_(H) FRS is conserved and therefore the orientation of V_(L) withrespect to V_(H) is fixed.

Genes coding for a number of Mabs are now available and the sequencescoding for the variable regions V_(L) and V_(H) have been determined. Itis thus possible to replace the latter sequences by DNA coding for V_(L)and V_(H) from different Mabs and indeed to construct the latter byincorporating DNA coding for chosen CDRs into DNA coding for a standardset of FRs. It is thus possible to construct genes coding for chimericanti-D Mabs having the CDRs from anti-D Mabs possessing particularlydesirable specificities or other properties and framework and constantregions derived from Mabs having other desirable properties.

It is a prerequisite of such construction that the amino acid sequencesof the CDR regions of the chosen anti-D Mabs and/or the genes coding forthem, should be known. The specific CDR gene sequences can then besynthesised, conveniently by chemical synthesis of the appropriateoligonucleotides, and incorporated into DNA sequences coding for astandard set of FRs and the human (or other) constant region. Of course,the FRs may be identical with those of the Mab providing the constantregion or, more conveniently, they may be a standard set of FRs whichcan be used generally in the synthesis of chimeric Mabs.

We have produced a number of anti-D Mabs of particular interest and havedetermined their amino acid sequences, thus making it possible for DNAsequences corresponding to their CDRs to be synthesised and incorporatedinto V_(H) and V_(L) sequences as described above. These may then becombined with DNA coding for the constant region to enable novel anti-DMabs to be synthesised which may have lower, the same or higher bindingability.

Thus, according to one aspect we provide DNA sequences comprisingoligonucleotides encoding CDR1, CDR2, and CDR3 regions of V_(H) (SEQ IDNOS:1-11, 12-22 and 23-34, respectively) and V_(L) (SEQ ID NOS:35-37,38-40 and 41-42, respectively) domains of antibodies against the humanRhD antigen, and functional equivalents thereof. In particular, we haveinvestigated and sequenced eleven Mabs, namely a) FOG-B, b) PAG-1, c)MAD-2, d) FOG-1, e) FOM-1, f) FOM-A, g) BRAD-3, h) JAC-10, i) GAD-2, J)REG-A, K) HAM-B, whose heavy and light chain sequences are representedin FIGS. 2-14, of the accompanying drawings, and which have both variedand particularly useful binding specificities. The FIGS. 2 and 3 showthe nucleotide and amino acid sequences of the light chain variabledomains of the Mabs FOG-B and PAG-1. Corresponding sequences for theheavy chain variable domains of these two Mabs are shown in FIGS. 4 and5, and sequences of the heavy chain variable domains of the Mabs MAD-2,FOG-1, FOM-A, BRAD-3, JAC-10, GAD-2, REG-A and HAM-B are shown in FIGS.6-14.

Synthetic genes, for both heavy and light chains may be created bycombining selected CDR 1, 2, and 3 regions, which may be selected fromdifferent antibody molecules having varied binding specificities.

Thus according to a further aspect, we provide DNA molecules coding forthe heavy or light chain fragments of a monoclonal antibody or fragmentthereof comprising CDR1, CDR2 and CDR3 encoding oligonucleotides fromantibodies FOG-B, PAG-1, MAD-2, FOG-1, FOM-1, FOM-A, BRAD-3, JAC-10,GAD-2, REG-A and HAM-B as illustrated in FIGS. 2-14.

In order to create functional genes, such oligonucleotides must beincorporated into a backbone sequence such that when expressed,functional proteins result.

Thus according to a further aspect, we provide DNA molecules comprisinga gene coding for the framework regions of a human antibody light orheavy chain having inserted therein in the correct CDR region,oligonucleotides encoding CDR1, CDR2 and CDR3 regions according to thepresent invention.

In the synthesis of a chimeric Mab in accordance with the invention,single stranded DNA coding for the V_(H) region of a chosen Mab (notnecessarily an anti-D Mab) is incorporated in single stranded form intoa vector capable of producing single stranded DNA, such as the M13bacteriophage. FIG. 1 shows diagrammatically the structure of a singlestranded V_(H) DNA including framework regions FR1 to FR4 withcomplementarity determining regions CDR1 to CDR3 of a Mab. These stepscan be accomplished by conventional techniques such as those describedin Riechmann et al (Nature, 332, 323-327, (1988)).

Three oligonucleotides may then be prepared corresponding to the CDRregions of the chosen anti-D Mab variable domain, eg the V_(H) region ofFOG-B as shown in FIG. 4, and will include several nucleotides on eitherside of each CDR region to permit hybridisation with the frameworkregions FR1 to FR4 (see FIG. 1). The sequences of the latter willnormally be substantially homologous with those of the anti-D Mab (e.g.FOG-B) but since the oligonucleotides will normally be synthesisedchemically, hybridisation may be ensured by matching the overlappingnucleotides exactly to the FRs 1 to 4. It may also be beneficial tomodify the oligonucleotides to express the CDRs more efficiently in theeventual host cells.

The three oligonucleotides, shown in FIG. 1 as oligo 1 to oligo 3, maythen be annealed to a single stranded V_(H) DNA in the M13 vector andused as primers to synthesise second strand DNA containing the anti-DV_(H) CDR sequences. This may be achieved conventionally using asuitable polymerase. Since the antibody specificity is determined solelyby the three CDR regions, the actual V_(H) gene chosen for the frameworktemplate is immaterial. All that is required is that there is sufficienthomology of the three chosen oligonucleotides with the template. This isensured by appropriate design of the terminal nucleotides of thesynthetic oligonucleotide primers. Thus the second strand may containsequences from substantially any human antibody heavy chain gene, solong as the resulting expressed protein posesses the desired bindingparameters.

The double stranded M13 vector may then be used to transform a suitablehost microorganism e.g. a conventional E. coli and one or more clonesselected which contain the required anti-D V_(H) specificity. Thecorrect clone may be identified by DNA seqencing.

The corresponding V_(L) DNA (e.g. for FOG-B) may be prepared in the sameway.

The DNA coding for the V_(H) and V_(L) regions may then be excised fromthe above vectors and introduced into other vectors.

According to a further aspect, we provide DNA molecules being syntheticgenes for chimaeric antibody, heavy or light chains when incorporatedinto vectors capable of expressing such antibody chains. Preferredvectors include mammalian expression vectors, such as pSV2gpt (heavychains) and pSV2neo (light chains) containing DNA coding for the humanconstant region. Such vectors are readily available from a number oflaboratories, or can readily be prepared by incorporating DNA coding forhuman constant region into known mammalian vectors.

The expression vectors so constructed may then be co-transfected into anappropriate cell-line e.g. a non-secreting IgG myeloma, for large scaleproduction.

Thus according to a yet further aspect, the present invention provideseach of the CDR polypeptides of the Mabs FOG-B, PAG-1, MAD-2, FOG-1,FOM-1, FOM-A, BRAD-3, JAC-I0, GAD-2, REG-A and HAM-B shown in FIGS. 2-14(SEQ ID NOS:43-55, respectively) of the accompanying drawings in singlestranded or double stranded form in the absence of the constant and orframework regions of said Mabs.

According to a yet further aspect, the invention provides chimaericantibody heavy and light chains of the variable domains comprising CDRpolypeptide sequences of the present invention.

Knowledge of the antibody sequences according to the invention enablesnew chimaeric anti-D antibody molecules to be prepared, havingappropriately designed binding specificities. These antibodies may beused for both therapy and diagnosis using presently known techniques.

According to a yet further aspect, we provide anti-RhD reagentscomprising at least one antibody molecule according to the invention.

According to a still yet further aspect, we provide pharmaceuticalcompositions for use in passive immunisation to prevent haemolyticdisease of the newborn comprising an antibody of the present inventiontogether with at least one phamacologically acceptable carrier ordiluent.

A sterile solution of such an antibody for human injection may beformulated in any physiologically acceptable aqueous medium, for exampleisotonic phosphate buffered saline or serum. Alternatively, the antibodymay be supplied in a freeze-dried formulation ready for reconstitutionprior to use.

EXAMPLE

(1) Construction of Chimaeric Antibody Genes

Three oligonucleotide primers are synthesised using an AppliedBiosystems machine according to the manufacturer's instructions andpurified on an 8M Urea/polyacrylamide gel (Sanger & Coulson, Febs Lett.,87, 107-110, 1978). The primers are designed to comprise in theircentral regions sequences complementary to the CDR1, CDR2 and CDR3regions of the anti-RhD antibody PAG-1 heavy chain gene, as identifiedaccording to the criteria described by Kabat et al. (Sequences ofProteins of Immunological Interest, U.S. Department of Health and SocialServices, 1987).

The central sequences are flanked at both their 5' and 3' termini bysequences of 10 nucleotides which hybridise to the termini of thecorresponding framework region sequences adjacent to the CDR sequence ofthe heavy chain antibody gene NEWM (Poljack et al., Biochemistry 16,3412-3420, 1977). The primers are then hybridised to the derived NEWMsingle stranded DNA heavy chain sequence in the M13 bacteriophage andthe complementary strand of the heavy chain variable region extendedusing DNA polymerase (Neuberger et al., Nature 314, 268-270 (1985),Jones et al., Nature 321, 522-5 (1986)). The M13 vector also contains anappropriate arrangement for ultimate expression, i.e. a leader sequence,and unique HindIII and BamHI restriction sites.

A similar construct is prepared from oligonucleotide primers homologousto the CDR regions of the PAG-1 anti-RhD antibody light chain genes, andutilising the M13 vector in which V_(L) and J_(L) regions of theantibody gene PAV1 (Sun et al., Nucleic Acids Research 13, 4921-4934,1985) are cloned.

(2) Expression of Antibody Polypeptides

The cloned genes for the V_(H) domains are excised using HindIII andBamHI and cloned into pSV2gpt (Mulligan and Berg, PNAS 78, 2072-6,1981). The cloned light chain genes are similarly excised and clonedinto pSV2neo (Southern and Berg, J. Molec. Appl. Genetics 1 327-381,1981). Sequences encloding IgG1 constant regions are then inserted intothe vectors (Riechmann et al., Nature 312, 323-7, (1988). Both vectorsare then transfected by electroporation (Potter et al., PNAS 81, 7161-3,1984) into the rat myeloma cell line YO (YB2/3.0 AG, 20) (Galfre andMilstein, Methods in Enzymology 73, 1-46, 1981) for antibody production.

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NO:4:                                       GTTTACTACTGGACC15                                                             (2) INFORMATION FOR SEQ ID NO:5:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:                                       GGTTACTACTGGAAC15                                                             (2) INFORMATION FOR SEQ ID NO:6:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 base 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        (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:                                       AGCTATGGCATGCAC15                                                             (2) INFORMATION FOR SEQ ID NO:10:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:                                      AATTATGGCATGCAC15                                                             (2) INFORMATION FOR SEQ ID NO:11:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:                                      AGCTATGGCATGCAC15                           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DESCRIPTION: SEQ ID NO:14:                                      GAAATCAATCATAGTGGAAGGACCAACTACAACCCGTCCCTCAAGACT48                            (2) INFORMATION FOR SEQ ID NO:15:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 48 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:                                      GAAATCAATCATAGTGGAGGCGCCAACTACAATCCGTCCCTCAAGAGT48                            (2) INFORMATION FOR SEQ ID NO:16:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 48 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:                                      GAAATCATTCATAGTGGAAGCACCAACTACAACCCGTCCCTCAAGAGT48                            (2) INFORMATION FOR SEQ ID NO:17:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 48 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:                                      GAAATCAGTCGTCGTGGAAGCACCAACTACAACCCGTCCCTCAAGAGT48                            (2) INFORMATION FOR SEQ ID NO:18:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 51 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:                                      CTTATATGGTATGATGGAAGTAATAAAGAATATGCAGACTTCGTGAAGGGC51                         (2) INFORMATION FOR SEQ ID NO:19:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 51 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:                                      CGTATTAATAGTTATGGAATTAGCACAAGTTACGCGAACTCCGTGAAGGGC51                         (2) INFORMATION FOR SEQ ID NO:20:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 51 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:                                      GTGATATGGTATGATGGAAGTAATAAGTACTATGCAGAGTCCGTGAAGGGC51                         (2) INFORMATION FOR SEQ ID NO:21:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 51 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:                                      GTTATATGGTATGATGGAAGTAATAAAAACTATGCAGACTCCGTGAAGGGC51                         (2) INFORMATION FOR SEQ ID NO:22:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 51 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:                                      GTTATTTGGTATGATGGAAGTAATAAATACTATGCAGACTCCGTGAAGGGC51                         (2) INFORMATION FOR SEQ ID NO:23:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 51 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:                                      CCAGGCTATGGCGACACCTCGGTACGGAAGAGGGTTTGGAATATGGACCTC51                         (2) INFORMATION FOR SEQ ID NO:24:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 48 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:                                      GTTTTGGTTTCCCGTACCATTTCACAGTACTCCTATTACATGGACGTC48                            (2) INFORMATION FOR SEQ ID NO:25:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 48 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:                                      GTTTTGGTTTCCCGTACGATTTCACAGTACTCCTATTACATGGACGTC48                            (2) INFORMATION FOR SEQ ID NO:26:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:                                      CTGTGGCTCGATGGACATGGGTACAAGTTTGACTAC36                                        (2) INFORMATION FOR SEQ ID NO:27:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 48 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:                                      GGCCGGTCCCGTTATAGTGGTTACGGCTTCTACTCCGGCATGGACGTC48                            (2) INFORMATION FOR SEQ ID NO:28:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 60 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:                                      GGCTTAGAACGTCCGATTAGGAACCAGCTGCTAAACCGTCTCGGTTACTACATGGACGTC60                (2) INFORMATION FOR SEQ ID NO:29:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 39 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:                                      GCCTTGGACTACATCTCCTTGGATTACGGTATGGACGTC39                                     (2) INFORMATION FOR SEQ ID NO:30:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 54 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:                                      GATAGTCCCAAAATGAGGGCTGGAAGTATGTTTCGCTACTACTACATGGACGTC54                      (2) INFORMATION FOR SEQ ID NO:31:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 51 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31:                                      GGAGAGCGCATAGCAGCTCGTCTCTTGTCGGGCGGGTACGGTATGGACGTC51                         (2) INFORMATION FOR SEQ ID NO:32:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 54 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32:                                      GTCGTTAGCAGCAACCGGTACTCTCTAAGCTACTATTATTACTACATGGACGTC54                      (2) INFORMATION FOR SEQ ID NO:33:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 51 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:                                      GAACGTACTACGATGTCTGGAGTGATCATTCCTCGCCGGTATTTTGACTAC51                         (2) INFORMATION FOR SEQ ID NO:34:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 48 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:                                      GAAGTTACTATGGTTCGGGGAGTTAGGCGTTACTACGGTATGGACGTC48                            (2) INFORMATION FOR SEQ ID NO:35:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 39 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:                                      TCCGGAACCAGCTCCAACATTGGGAATAATTATGTATCC39                                     (2) INFORMATION FOR SEQ ID NO:36:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 33 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:                                      GGGGGAAACAACATTGGGCGTAAAAGTGTGCAC33                                           (2) INFORMATION FOR SEQ ID NO:37:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 33 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:                                      GGGGGAAACAACATTGGACGTAAAAGTGTGCAC33                                           (2) INFORMATION FOR SEQ ID NO:38:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:                                      GACAATAATAAGCGACCCTCA21                                                       (2) INFORMATION FOR SEQ ID NO:39:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:                                      GGTGCTAGCGAGCGGCCCTCA21                                                       (2) INFORMATION FOR SEQ ID NO:40:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40:                                      GGTGCTAGCGACCGGCCCTCA21                                                       (2) INFORMATION FOR SEQ ID NO:41:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 33 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41:                                      GCAACATGGGATAGCAGCCTGAGTGCTGTGGTG33                                           (2) INFORMATION FOR SEQ ID NO:42:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 39 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:                                      CAGGTGTGGGATAGTAGTAGTGCTCATCCGGGGGTGGTA39                                     (2) INFORMATION FOR SEQ ID NO:43:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 333 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43:                                      CAGTCTGTGTTGACGCAGCCGCCCTGAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATC60                TCCTGCTCCGGAACCAGCTCCAACATTGGGAATAATTATGTATCCTGGTATCAGCAGCTC120               CCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCT180               GACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCGG240               ACTGGGGACGAGGCCGATTATTACTGCGCAACATGGGATAGCAGCCTGAGTGCTGTGGTG300               TTCGGCGGAGGGACCAAGCTGACCGTCCTAAGT333                                          (2) INFORMATION FOR SEQ ID NO:44:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 333 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44:                                      TCCTATGTGCTGACTCAGCCACCCTCGGTGTCAGTGGCCCCAGGACAGACGGCCAGGATT60                ACCTGTGGGGGAAACAACATTGGACGTAAAAGTGTGCACTGGTACCAGCAGAAGCCAGGC120               CAGGCCCCTGTGCTGGTCGTCTATGGTGCTAGCGACCGGCCCTCAGGGATCCCTGAGCGA180               TTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACCATCAGCAGGGTCGCAGCCGGG240               GATGAGGCCGACTATTACTGTCAGGTGTGGGATAGTAGTAGTGCTCATCCGGGGGTGGTA300               TTCGGCGGAGGGACCAAGCTGACCGTCCTAGGT333                                          (2) INFORMATION FOR SEQ ID NO:45:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 381 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:45:                                      CAGCTGCGGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTC60                ACCTGCAGTGTCTCTGGTGGCTCCGTCAGCAGTGGTGGTCTCTACTGGGGCTGGGTCCGC120               CAGCCCCCAGGGAAGGGGCTCGAATGGATTGGCAGTATATTTTATAGTGGGAGCACCTAC180               TACAATCCCTCCCTCAAGAGCCGAGTCACCATATCCGTAGACACGTTGAAGAATAACTTC240               TCCCTGAAGCTGAGTTCTGTGACCGCCGCAGACACGGCTGTTTATTACTGTACGAGACCA300               GGCTATGGCGACACCTCGGTACGGAAGAGGGTTTGGAATATGGACCTCTGGGGCCAAGGG360               ACCACGGTCACCGTCTCCTCG381                                                      (2) INFORMATION FOR SEQ ID NO:46:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 372 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46:                                      CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCGTC60                ACCTGCACTGTCTCTGGTGGCTCCGTCAGTAGTTCCTACTGGAGCTGGATCCGGCAGCCC120               CCAGGGAAGGGACCGGAGTGGATTGGGTATATCTATTACAGTGGGAGCACCAACTACAAC180               CCCTCCCTCAGGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCCCTG240               AAGCTGGGCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCGAGAGTTTTGGTT300               TCCCGTACGATTTCACAGTACTCCTATTACATGGACGTCTGGGGCAAAGGGACCACGGTC360               ACCGTGTCCTCA372                                                               (2) INFORMATION FOR SEQ ID NO:47:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 321 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (B) LOCATION: 1..321                                                          (D) OTHER INFORMATION: /note= "Nucleotides 1-321 corres.                      to nucleotides 24-344 of Fig. 6/14. Nucleotides                               1-23 and 345- 360 represent PCR primers."                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:47:                                      CGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCGCTGTCTATGGTGGGTC60                CTTCAGTGGTTACTACTGGAGCTGGATCCGCCAGCCTCCAGGGAAGGGGCTGGAGTGGAT120               TGGGGAAATCAATCATAGTGGAAGGACCAACTACAACCCGTCCCTCAAGACTCGAGTCAC180               CATATCAGTAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGTTCTGTGACCGCCGC240               GGACACGGCTGTGTATTACTGTGCGAGACTGTGGCTCGATGGACATGGGTACAAGTTTGA300               CTACTGGGGCCAGGGAACCCT321                                                      (2) INFORMATION FOR SEQ ID NO:48:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 372 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:48:                                      CAGGTGCATCTACAGCAGTGGGGCACAGGGCTGTTGAAGCCTTCGGAGACCCTGTCCCTC60                ACCTGCGCTGTCCATGGTGGGTCCTTCAATGTTTACTACTGGACCTGGATCCGCCAGCCC120               CCAGGAAAGGCGCTGGAGTGGATTGGGGAAATCAATCATAGTGGAGGCGCCAACTACAAT180               CCGTCCCTCAAGAGTCGAGTCACCATGTCAGCAGACACGTCCAAGAACCAGTTCTCCCTG240               AAACTGACCTCTGTGACCGCCGCGGACACGGCTGTGTTTTATTGTGCGAGAGGCCGGTCC300               CGTTATAGTGGTTACGGCTTCTACTCCGGCATGGACGTCTGGGGCCCAGGGACCACGGTC360               ACCGTCTCCTCA372                                                               (2) INFORMATION FOR SEQ ID NO:49:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 384 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49:                                      CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCCCTC60                ACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTACTACTGGAACTGGATCCGCCAGCCC120               CCAGGGAAGGGGCTGGAGTGGATTGGGGAAATCATTCATAGTGGAAGCACCAACTACAAC180               CCGTCCCTCAAGAGTCGAGTCACCATGTCAGTAGACACGTCCAAGAACCAGTTCTCCCTG240               AAGCTGAGCTCTGTGACCGCCGCGGACACGGCTGTGTATTACTGTGCGAGAGGCTTAGAA300               CGTCCGATTAGGAACCAGCTGCTAAACCGTCTCGGTTACTACATGGACGTCTGGGGCAAA360               GGGACCACGGTCACCGTCTCCTCA384                                                   (2) INFORMATION FOR SEQ ID NO:50:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 363 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:50:                                      CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCCCTC60                ACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTACTACTGGAGCTGGATCCGCCAGCCC120               CCAGGGAAGGGGCTGGAGTGGATTGGGGAAATCAGTCGTCGTGGAAGCACCAACTACAAC180               CCGTCCCTCAAGAGTCGAGTCGCCATATCAGTAGACACGTCCAAGAACCAGTTCTCCCTG240               AAGGTGAGGTCTGTGACCGCCGCGGACACGGCTGTGTATTACTGTGCGAGAGCCTTGGAC300               TACATCTCCTTGGATTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCC360               TCA363                                                                        (2) INFORMATION FOR SEQ ID NO:51:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 342 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (B) LOCATION: 1..342                                                          (D) OTHER INFORMATION: /note= "Nucleotides 1-381 corres.                      to nucleotides 24-365 of Fig. 10/14. Nucleotides                              1-23 and 366- 381 represent PCR primers."                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51:                                      GGGAGGCGTGGTCCAGCCTGGGAGGTTCCTGAGACTCTCCTGTGCAGCGTCTGGATTCAC60                CTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGT120               GGCACTTATATGGTATGATGGAAGTAATAAAGAATATGCAGACTTCGTGAAGGGCCGATT180               CACCATCTCCAGAGACAATTCCAAGAATACACTGTATCTGCAAATGAACAGCCTGAGAGC240               CGAGGACACGGCTGTGTATTACTGTGCGACAGATAGTCCCAAAATGAGGGCTGGAAGTAT300               GTTTCGCTACTACTACATGGACGTCTGGGGCAAAGGGACCAC342                                 (2) INFORMATION FOR SEQ ID NO:52:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 339 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (B) LOCATION: 1..339                                                          (D) OTHER INFORMATION: /note= "Nucleotides 1-378 corres.                      to nucleotides 24-362 of Fig. 11/14. Nucleotides                              1-23 and 363- 378 represent PCR primers."                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:52:                                      GGGAGGCTTAGTTCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAC60                CTTCAGTAGTTACTGGATGCACTGGGTCCGCCAAGCTCCAGGGAAGGGGCTGGTGTGGGT120               CTCACGTATTAATAGTTATGGAATTAGCACAAGTTACGCGAACTCCGTGAAGGGCCGATT180               CACCATCTCCAGAGACAACGCCAAGAACACGCTGTATCTGCAAATGAACACTCTGAGAGC240               CGAGGACACGGCTGTGTATTACTGTGCAAGAGGAGAGCGCATAGCAGCTCGTCTCTTGTC300               GGGCGGGTACGGTATGGACGTCTGGGGCCAAGGGACCAC339                                    (2) INFORMATION FOR SEQ ID NO:53:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 342 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (B) LOCATION: 1..342                                                          (D) OTHER INFORMATION: /note= "Nucleotides 1-381 corres.                      to nucleotides 24-365 of Fig. 12/14. Nucleotides                              1-23 and 366- 381 represent PCR primers."                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53:                                      GGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCAC60                CTTTAGTAGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGT120               GGCAGTGATATGGTATGATGGAAGTAATAAGTACTATGCAGAGTCCGTGAAGGGCCGATT180               CACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGC240               CGAGGACACGGCTGTGTATTACTGTGCGAGAGTCGTTAGCAGCAACCGGTACTCTCTAAG300               CTACTATTATTACTACATGGACGTCTGGGGCAAAGGGACCAC342                                 (2) INFORMATION FOR SEQ ID NO:54:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 339 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (B) LOCATION: 1..339                                                          (D) OTHER INFORMATION: /note= "Nucleotides 1-378 corres.                      to nucleotides 24-362 of Fig. 13/14. Nucleotides                              1-23 and 363- 378 represent PCR primers."                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54:                                      GGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCAC60                CTTCAATAATTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGT120               GGCAGTTATATGGTATGATGGAAGTAATAAAAACTATGCAGACTCCGTGAAGGGCCGATT180               CACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGC240               CGAGGACACGGCTGTGTATTACTGTGCGAGAGAACGTACTACGATGTCTGGAGTGATCAT300               TCCTCGCCGGTATTTTGACTACTGGGGCCAGGGAACCCG339                                    (2) INFORMATION FOR SEQ ID NO:55:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 335 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: DNA (genomic)                                             (ix) FEATURE:                                                                 (A) NAME/KEY: misc.sub.-- feature                                             (B) LOCATION: 1..335                                                          (D) OTHER INFORMATION: /note= "Nucleotides 1-375 corres.                      to nucleotides 24-359 of Fig. 14/14. Nucleotides                              1-23 and 360- 375 represent PCR primers."                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:55:                                      GGGGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACC60                TTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTG120               GCAGTTATTTGGTATGATGGAAGTAATAAATACTATGCAGACTCCGTGAAGGGCCGATTC180               ACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCC240               GAGGACACGGCTGTGTATTACTGTGCGAGAGAAGTTACTATGGTTCGGGGAGTTAGGCGT300               TACTACGGTATGGACGTCTGGGGCCCAGGGACCAC335                                        __________________________________________________________________________

I claim:
 1. An isolated, synthetic or recombinant DNA moleculecomprising a nucleotide sequence encoding a V_(H) domain of an antibodyagainst the human RhD antigen, said V_(H) domain comprising a CDR1, CDR2and a CDR3 region, wherein said V_(H) domain is selected from the groupconsisting of:(i) a V_(H) domain comprising a CDR1 region encoded by theDNA sequence of AGTGGTGGTCTCTACTGGGGC; a CDR2 region encoded by the DNAsequence of AGTATATTTTATAGTGGGAGCACCTACTACAATCCCTC CCTCAAGAGC; and aCDR3 region encoded by the DNA sequence ofCCAGGCTATGGCGACACCTCGGTACGGAAGAGGGTTTGGAATATGGACCTC; (ii) a V_(H) domaincomprising a CDR1 region encoded by the DNA sequence of AGTTCCTACTGGAGC;a CDR2 region encoded by the DNA sequence ofTATATCTATTACAGTGGGAGCACCAACTACAACCCCTCCCTC AGGAGT; and a CDR3 regionencoded by the DNA sequence ofGTTTTGGTTTCCCGTACGATTTCACAGTACTCCTATTACATGGACGTC; (iii) a V_(H) domaincomprising a CDR1 region encoded by the DNA sequence of GTTTACTACTGGACC;a CDR2 region encoded by the DNA sequence ofGAAATCAATCATAGTGGAGGCGCCAACTACAATCCGTCC CTCAAGAGT; and a CDR3 regionencoded by the DNA sequence ofGGCCGGTCCCGTTATAGTGGTTACGGCTTCTACTCCGGCATGGACGTC; (iv) a V_(H) domaincomprising a CDR1 region encoded by the DNA sequence of GGTTACTACTGGAGC;a CDR2 region encoded by the DNA sequence ofGAAATCAGTCGTCGTGGAAGCACCAACTACAACCCGTCCCTC AAGAGT; and a CDR3 regionencoded by the DNA sequence of GCCTTGGACTACATCTCCTTGGATTACGGTATGGACGTC;(v) a V_(H) domain comprising a CDR1 region encoded by the DNA sequenceof AGCTATGGCATGCAC; a CDR2 region encoded by the DNA sequence ofCTTATATGGTATGATGGAAGTAATAAAGAATATGCAGACTTC GTGAAGGGC; and a CDR3 regionencoded by the DNA sequence ofGATAGTCCCAAAATGAGGGCTGGAAGTATGTTTCGCTACTACTACATGGACGTC; (vi) a V_(H)domain comprising a CDR1 region encoded by the DNA sequence ofAGTTACTGGATGCAC; a CDR2 region encoded by the DNA sequence ofCGTATTAATAGTTATGGAATTAGCACAAGTTACGCGAACTCC GTGAAGGGC; and a CDR3 regionencoded by the DNA sequence ofGGAGAGCGCATAGCAGCTCGTCTCTTGTCGGGCGGGTACGGTATGGACGTC; (vii) a V_(H)domain comprising a CDR1 region encoded by the DNA sequence ofAGCTATGGCATGCAC; a CDR2 region encoded by the DNA sequence ofGTGATATGGTATGATGGAAGTAATAAGTACTATGCAGAGTCC GTGAAGGGC; and a CDR3 regionencoded by the DNA sequence ofGTCGTTAGCAGCAACCGGTACTCTCTAAGCTACTATTATTACTACATGGACGTC; (viii) a V_(H)domain comprising a CDR1 region encoded by the DNA sequence ofAATTATGGCATGCAC; a CDR2 region encoded by the DNA sequence ofGTTATATGGTATGATGGAAGTAATAAAAACTATGCAGACTCC GTGAAGGGC; and a CDR3 regionencoded by the DNA sequence ofGAACGTACTACGATGTCTGGAGTGATCATTCCTCGCCGGTATTTTGACTAC; and (ix) a V_(H)domain comprising a CDR1 region encoded by the DNA sequence ofAGCTATGGCATGCAC; a CDR2 region encoded by the DNA sequence ofGTTATTTGGTATGATGGAAGTAATAAATACTATGCAGACTCC GTGAAGGGC; and a CDR3 regionencoded by the DNA sequence ofGAAGTTACTATGGTTCGGGGAGTTAGGCGTTACTACGGTATGGACGTC,or a DNA moleculewherein at least one of said sequences has extended terminal regions. 2.A DNA molecule according to claim 1, wherein said V_(H) domain comprisesa CDR1 region encoded by the DNA sequence of AGTGGTGGTCTCTACTGGGGC; aCDR2 region encoded by the DNA sequence ofAGTATATTTTATAGTGGGAGCACCTACTACAATCCCTC CCTCAAGAGC; and a CDR3 regionencoded by the DNA sequence ofCCAGGCTATGGCGACACCTCGGTACGGAAGAGGGTTTGGAATATGGACCTC.
 3. A DNA moleculeaccording to claim 1, wherein said V_(H) domain comprises a V_(H) domaincomprising a CDR1 region encoded by the DNA sequence of AGTTCCTACTGGAGC;a CDR2 region encoded by the DNA sequence ofTATATCTATTACAGTGGGAGCACCAACTACAACCCCTCCCTC AGGAGT; and a CDR3 regionencoded by the DNA sequence ofGTTTTGGTTTCCCGTACGATTTCACAGTACTCCTATTACATGGACGTC.
 4. A DNA moleculeaccording to claim 1, wherein said V_(H) domain comprises a CDR1 regionencoded by the DNA sequence of GTTTACTACTGGACC; a CDR2 region encoded bythe DNA sequence of GAAATCAATCATAGTGGAGGCGCCAACTACAATCCGTCC CTCAAGAGT;and a CDR3 region encoded by the DNA sequence ofGGCCGGTCCCGTTATAGTGGTTACGGCTTCTACTCCGGCATGGACGTC.
 5. A DNA moleculeaccording to claim 1, wherein said V_(H) domain comprises a CDR1 regionencoded by the DNA sequence of GGTTACTACTGGAGC; a CDR2 region encoded bythe DNA sequence of GAAATCAGTCGTCGTGGAAGCACCAACTACAACCCGTCCCTCAAGAGT;and a CDR3 region encoded by the DNA sequence ofGCCTTGGACTACATCTCCTTGGATTACGGTATGGACGTC.
 6. A DNA molecule according toclaim 1, wherein said V_(H) domain comprises a CDR1 region encoded bythe DNA sequence of AGCTATGGCATGCAC; a CDR2 region encoded by the DNAsequence of CTTATATGGTATGATGGAAGTAATAAAGAATATGCAGACTTC GTGAAGGGC; and aCDR3 region encoded by the DNA sequence ofGATAGTCCCAAAATGAGGGCTGGAAGTATGTTTCGCTACTACTACATGGACGTC.
 7. A DNAmolecule according to claim 1, wherein said V_(H) domain comprises aCDR1 region encoded by the DNA sequence of AGTTACTGGATGCAC; a CDR2region encoded by the DNA sequence ofCGTATTAATAGTTATGGAATTAGCACAAGTTACGCGAACTCC GTGAAGGGC; and a CDR3 regionencoded by the DNA sequence ofGGAGAGCGCATAGCAGCTCGTCTCTTGTCGGGCGGGTACGGTATGGACGTC.
 8. A DNA moleculeaccording to claim 1, wherein said V_(H) domain comprises a CDR1 regionencoded by the DNA sequence of AGCTATGGCATGCAC; a CDR2 region encoded bythe DNA sequence of GTGATATGGTATGATGGAAGTAATAAGTACTATGCAGAGTCCGTGAAGGGC; and a CDR3 region encoded by the DNA sequence ofGTCGTTAGCAGCAACCGGTACTCTCTAAGCTACTATTATTACTACATGGACGTC.
 9. A DNAmolecule according to claim 1, wherein said V_(H) domain comprises aCDR1 region encoded by the DNA sequence of AATTATGGCATGCAC; a CDR2region encoded by the DNA sequence ofGTTATATGGTATGATGGAAGTAATAAAAACTATGCAGACTCC GTGAAGGGC; and a CDR3 regionencoded by the DNA sequence ofGAACGTACTACGATGTCTGGAGTGATCATTCCTCGCCGGTATTTTGACTAC.
 10. A DNA moleculeaccording to claim 1, wherein said V_(H) domain comprises a CDR1 regionencoded by the DNA sequence of AGCTATGGCATGCAC; a CDR2 region encoded bythe DNA sequence of GTTATTTGGTATGATGGAAGTAATAAATACTATGCAGACTCCGTGAAGGGC; and a CDR3 region encoded by the DNA sequence ofGAAGTTACTATGGTTCGGGGAGTTAGGCGTTACTACGGTATGGACGTC.
 11. The DNA moleculeaccording to claim 1, further comprising a nucleotide sequence encodinga V_(L) domain of the antibody comprising a CDR1, CDR2 and a CDR3region, wherein said V_(L) domain is selected from the group consistingof:(i) a V_(L) domain comprising a CDR1 region encoded by the DNAsequence TCCGGAACCAGCTCCAACATTGGGAATAATTATGTATCC; a CDR2 region encodedby the DNA sequence GACAATAATAAGCGACCC TCA; and a CDR3 region encoded bythe DNA sequence GCAACATGGGATAGCAGCCTGAGTGCTGTGGTG; and (ii) a V_(L)domain comprising a CDR1 region encoded by the DNA sequenceGGGGGAAACAACATTGGACGTAAAAGTGTGCAC; a CDR2 region encoded by the DNAsequence GGTGCTAGCGACCGGCCCTCA; and a CDR3 region encoded by the DNAsequence CAGGTGTGGGATAGTAGT AGTGCTCATCCGGGGGTGGTA.
 12. An isolated,synthetic or recombinant DNA molecule comprising a nucleotide sequenceencoding a V_(L) domain of an antibody against the human RhD antigen,said V_(L) domain comprising a CDR1, CDR2 and a CDR3 region, whereinsaid V_(L) domain is selected from the group consisting of:(i) a V_(L)domain comprising a CDR1 region encoded by the DNA sequenceTCCGGAACCAGCTCCAACATTGGGAATAATTATGTATCC; a CDR2 region encoded by theDNA sequence GACAATAATAAGCGACCC TCA; and a CDR3 region encoded by theDNA sequence GCAACATGGGATAGCAGCCTGAGTGCTGTGGTG; and (ii) a V_(L) domaincomprising a CDR1 region encoded by the DNA sequenceGGGGGAAACAACATTGGACGTAAAAGTGTGCAC; a CDR2 region encoded by the DNAsequence GGTGCTAGCGACCGGCCCTCA; and a CDR3 region encoded by the DNAsequence CAGGTGTGGGATAGTAGT AGTGCTCATCCGGGGGTGGTA,or a DNA moleculewherein at least one of said sequences has extended terminal regions.13. The DNA molecule according to claim 12, wherein said V_(L) domaincomprises a CDR1 region encoded by the DNA sequenceTCCGGAACCAGCTCCAACATTGGGAATAATTATGTATCC; a CDR2 region encoded by theDNA sequence GACAATAATAAGCGACCC TCA; and a CDR3 region encoded by theDNA sequence GCAACATGGGATAGCAGCCTGAGTGCTGTGGTG.
 14. The DNA moleculeaccording to claim 12, wherein said V_(L) domain comprises a CDR1 regionencoded by the DNA sequence GGGGGAAACAACATTGGACGTAAAAGTGTGCAC; a CDR2region encoded by the DNA sequence GGTGCTAGCGACCGGCCCTCA; and a CDR3region encoded by the DNA sequence CAGGTGTGGGATAGTAGTAGTGCTCATCCGGGGGTGGTA.
 15. The DNA molecule according to claim 12, furthercomprising a nucleotide sequence encoding a V_(H) domain comprising aCDR1, CDR2 and a CDR3 region, wherein said V_(H) domain is selected fromthe group consisting of:(i) a V_(H) domain comprising a CDR1 regionencoded by the DNA sequence of AGTGGTGGTCTCTACTGGGGC; a CDR2 regionencoded by the DNA sequence of AGTATATTTTATAGTGGGAGCACCTACTACAATCCCTCCCTCAAGAGC; and a CDR3 region encoded by the DNA sequence ofCCAGGCTATGGCGACACCTCGGTACGGAAGAGGGTTTGGAATATGGACCTC; (ii) a V_(H) domaincomprising a CDR1 region encoded by the DNA sequence of AGTTCCTACTGGAGC;a CDR2 region encoded by the DNA sequence ofTATATCTATTACAGTGGGAGCACCAACTACAACCCCTCCCTC AGGAGT; and a CDR3 regionencoded by the DNA sequence ofGTTTTGGTTTCCCGTACGATTTCACAGTACTCCTATTACATGGACGTC; (iii) a V_(H) domaincomprising a CDR1 region encoded by the DNA sequence of GTTTACTACTGGACC;a CDR2 region encoded by the DNA sequence ofGAAATCAATCATAGTGGAGGCGCCAACTACAATCCGTCC CTCAAGAGT; and a CDR3 regionencoded by the DNA sequence ofGGCCGGTCCCGTTATAGTGGTTACGGCTTCTACTCCGGCATGGACGTC; (iv) a V_(H) domaincomprising a CDR1 region encoded by the DNA sequence of GGTTACTACTGGAGC;a CDR2 region encoded by the DNA sequence ofGAAATCAGTCGTCGTGGAAGCACCAACTACAACCCGTCCCTC AAGAGT; and a CDR3 regionencoded by the DNA sequence of GCCTTGGACTACATCTCCTTGGATTACGGTATGGACGTC;(v) a V_(H) domain comprising a CDR1 region encoded by the DNA sequenceof AGCTATGGCATGCAC; a CDR2 region encoded by the DNA sequence ofCTTATATGGTATGATGGAAGTAATAAAGAATATGCAGACTTC GTGAAGGGC; and a CDR3 regionencoded by the DNA sequence ofGATAGTCCCAAAATGAGGGCTGGAAGTATGTTTCGCTACTACTACATGGACGTC; (vi) a V_(H)domain comprising a CDR1 region encoded by the DNA sequence ofAGTTACTGGATGCAC; a CDR2 region encoded by the DNA sequence ofCGTATTAATAGTTATGGAATTAGCACAAGTTACGCGAACTCC GTGAAGGGC; and a CDR3 regionencoded by the DNA sequence ofGGAGAGCGCATAGCAGCTCGTCTCTTGTCGGGCGGGTACGGTATGGACGTC; (vii) a V_(H)domain comprising a CDR1 region encoded by the DNA sequence ofAGCTATGGCATGCAC; a CDR2 region encoded by the DNA sequence ofGTGATATGGTATGATGGAAGTAATAAGTACTATGCAGAGTCC GTGAAGGGC; and a CDR3 regionencoded by the DNA sequence ofGTCGTTAGCAGCAACCGGTACTCTCTAAGCTACTATTATTACTACATGGACGTC; (viii) a V_(H)domain comprising a CDR1 region encoded by the DNA sequence ofAATTATGGCATGCAC; a CDR2 region encoded by the DNA sequence ofGTTATATGGTATGATGGAAGTAATAAAAACTATGCAGACTCC GTGAAGGGC; and a CDR3 regionencoded by the DNA sequence ofGAACGTACTACGATGTCTGGAGTGATCATTCCTCGCCGGTATTTTGACTAC; and (ix) a V_(H)domain comprising a CDR1 region encoded by the DNA sequence ofAGCTATGGCATGCAC; a CDR2 region encoded by the DNA sequence ofGTTATTTGGTATGATGGAAGTAATAAATACTATGCAGACTCC GTGAAGGGC; and a CDR3 regionencoded by the DNA sequence ofGAAGTTACTATGGTTCGGGGAGTTAGGCGTTACTACGGTATGGACGTC.
 16. An isolated,synthetic or recombinant DNA molecule encoding a gene which codes forthe framework region of a human antibody heavy chain having insertedtherein a CDR1, CDR2 and a CDR3 region, wherein the combination of saidCDR1, CDR2 and CDR3 regions is selected from the group consisting of:(i)a CDR1 region encoded by the DNA sequence of AGTGGTGGTCTCTACTGGGGC; aCDR2 region encoded by the DNA sequence ofAGTATATTTTATAGTGGGAGCACCTACTACAATCCCTC CCTCAAGAGC; and a CDR3 regionencoded by the DNA sequence ofCCAGGCTATGGCGACACCTCGGTACGGAAGAGGGTTTGGAATATGGACCTC; (ii) a CDR1 regionencoded by the DNA sequence of AGTTCCTACTGGAGC; a CDR2 region encoded bythe DNA sequence of TATATCTATTACAGTGGGAGCACCAACTACAACCCCTCCCTC AGGAGT;and a CDR3 region encoded by the DNA sequence ofGTTTTGGTTTCCCGTACGATTTCACAGTACTCCTATTACATGGACGTC; (iii) a CDR1 regionencoded by the DNA sequence of GTTTACTACTGGACC; a CDR2 region encoded bythe DNA sequence of GAAATCAATCATAGTGGAGGCGCCAACTACAATCCGTCC CTCAAGAGT;and a CDR3 region encoded by the DNA sequence ofGGCCGGTCCCGTTATAGTGGTTACGGCTTCTACTCCGGCATGGACGTC; (iv) a CDR1 regionencoded by the DNA sequence of GGTTACTACTGGAGC; a CDR2 region encoded bythe DNA sequence of GAAATCAGTCGTCGTGGAAGCACCAACTACAACCCGTCCCTC AAGAGT;and a CDR3 region encoded by the DNA sequence ofGCCTTGGACTACATCTCCTTGGATTACGGTATGGACGTC; (v) a CDR1 region encoded bythe DNA sequence of AGCTATGGCATGCAC; a CDR2 region encoded by the DNAsequence of CTTATATGGTATGATGGAAGTAATAAAGAATATGCAGACTTC GTGAAGGGC; and aCDR3 region encoded by the DNA sequence ofGATAGTCCCAAAATGAGGGCTGGAAGTATGTTTCGCTACTACTACATGGACGTC; (vi) a CDR1region encoded by the DNA sequence of AGTTACTGGATGCAC; a CDR2 regionencoded by the DNA sequence ofCGTATTAATAGTTATGGAATTAGCACAAGTTACGCGAACTCC GTGAAGGGC; and a CDR3 regionencoded by the DNA sequence ofGGAGAGCGCATAGCAGCTCGTCTCTTGTCGGGCGGGTACGGTATGGACGTC; (vii) a CDR1 regionencoded by the DNA sequence of AGCTATGGCATGCAC; a CDR2 region encoded bythe DNA sequence of GTGATATGGTATGATGGAAGTAATAAGTACTATGCAGAGTCCGTGAAGGGC; and a CDR3 region encoded by the DNA sequence ofGTCGTTAGCAGCAACCGGTACTCTCTAAGCTACTATTATTACTACATGGACGTC; (viii) a CDR1region encoded by the DNA sequence of AATTATGGCATGCAC; a CDR2 regionencoded by the DNA sequence ofGTTATATGGTATGATGGAAGTAATAAAAACTATGCAGACTCC GTGAAGGGC; and a CDR3 regionencoded by the DNA sequence ofGAACGTACTACGATGTCTGGAGTGATCATTCCTCGCCGGTATTTTGACTAC; and (ix) a CDR1region encoded by the DNA sequence of AGCTATGGCATGCAC; a CDR2 regionencoded by the DNA sequence ofGTTATTTGGTATGATGGAAGTAATAAATACTATGCAGACTCC GTGAAGGGC; and a CDR3 regionencoded by the DNA sequence ofGAAGTTACTATGGTTCGGGGAGTTAGGCGTTACTACGGTATGGACGTC,or a DNA moleculewherein at least one of said sequences has extended terminal regions.17. An isolated, synthetic or recombinant DNA molecule encoding a genewhich codes for the framework region of a human antibody light chainhaving inserted therein a CDR1, CDR2 and a CDR3 region, wherein thecombination of said CDR1, CDR2 and CDR3 regions is selected from thegroup consisting of:(i) a CDR1 region encoded by the DNA sequenceTCCGGAACCAGCTCCAACATTGGGAATAATTATGTATCC; a CDR2 region encoded by theDNA sequence GACAATAATAAGCGACCC TCA; and a CDR3 region encoded by theDNA sequence GCAACATGGGATAGCAGCCTGAGTGCTGTGGTG; and (ii) a CDR1 regionencoded by the DNA sequence GGGGGAAACAACATTGGACGTAAAAGTGTGCAC; a CDR2region encoded by the DNA sequence GGTGCTAGCGACCGGCCCTCA; and a CDR3region encoded by the DNA sequence CAGGTGTGGGATAGTAGTAGTGCTCATCCGGGGGTGGTA,or a DNA molecule wherein at least one of saidsequences has extended terminal regions.
 18. A vector comprising the DNAmolecule of claim 16 operably linked in proper reading frame tosequences which direct the expression of the V_(H) domain encoded bysaid DNA molecule.
 19. The vector of claim 18, wherein said vector is apSV2gpt vector.
 20. The vector of claim 18, wherein said vector isreplicable in mammalian cells.
 21. A vector comprising the DNA moleculeof claim 12 operably linked in proper reading frame to sequences whichdirect the expression of the V_(L) domain encoded by said DNA molecule.22. The vector of claim 21, wherein said vector is a pSV2neo vector. 23.The vector of claim 21, wherein said vector is replicable in mammaliancells.